Search

JP-7856262-B2 - Modulators for immune evasion mechanisms in universal cell therapy

JP7856262B2JP 7856262 B2JP7856262 B2JP 7856262B2JP-7856262-B2

Inventors

  • アリシ，エヴレン
  • フセイン，アラムダール

Assignees

  • ヴィセリックス・インコーポレーティッド

Dates

Publication Date
20260511
Application Date
20201207
Priority Date
20191205

Claims (13)

  1. It is a therapeutic agent, It contains cells or extracellular vesicles expressing one or more CD45-binding molecules configured to inhibit functional immunological synapse formation with cytotoxic cells, thereby preventing cytotoxicity. The one or more CD45-binding molecules include a recombinant protein comprising, in this order: (i) a signal peptide, (ii) a heavy chain of an anti- CD45 antibody, (iii) a first linker, (iv) a light chain of an anti-CD45 antibody , ( vi) a stalk, and (vii) a transmembrane region. The first linker contains an SGGGG motif and/or its length varies over 5 to 60 amino acids. The aforementioned stalk has a length of 8 to 200 amino acids. A therapeutic agent wherein the transmembrane region is derived from CD34, CD45, CD28, and/or CD8a .
  2. The therapeutic agent according to claim 1, wherein the recombinant protein comprises in this order: (i) a signal peptide, (ii) a heavy chain of an anti-CD45 antibody, (iii) a first linker, (iv) a light chain of an anti-CD45 antibody, (v) a second linker having a length of 5 to 60 amino acids, (vi) a stalk , (vii) a transmembrane region, and ( viiii) an intracellular region.
  3. The therapeutic agent according to claim 1 , wherein one or more CD45-binding molecules contain a single-chain antibody .
  4. The therapeutic agent according to claim 1, comprising extracellular vesicles .
  5. The therapeutic agent according to claim 1, comprising a protein having the sequence described in SEQ ID NO: 5, 54, 56, 58, or 60 , or a protein having at least 80% identity with SEQ ID NO: 5, 54, 56, 58, or 60.
  6. The therapeutic agent according to claim 1, comprising cells having one or more CD45-binding molecules expressed on the surface of the cells.
  7. The therapeutic agent according to claim 6 , wherein the cells include graft cells.
  8. The therapeutic agent according to claim 6, wherein one or more CD45-binding molecules can retain CD45 in developing immunological synapses on the surface of the cytotoxic cells, thereby interfering with the formation of functional immunological synapses.
  9. A therapeutic agent according to any one of claims 1 to 8 , for use as a pharmaceutical.
  10. A therapeutic agent according to any one of claims 1 to 8, for use in the prevention or treatment of one or more conditions of autoimmune diseases, hematological cancers, bone marrow failure syndromes, hereditary immune disorders, abnormal hemoglobin disorders, neurological disorders, and graft-versus- host diseases.
  11. A therapeutic agent according to any one of claims 1 to 8 , for use in the prevention or treatment of one or more of psoriasis and vitiligo, for promoting escape from T cell-mediated lysis.
  12. A therapeutic agent according to any one of claims 1 to 8 , wherein graft-versus-host disease is prevented when xenocellular cells for transplantation are exposed to the therapeutic agent.
  13. The therapeutic agent according to any one of claims 1 to 8, wherein the cell or extracellular vesicle is bound to the surface of a different cell.

Description

Cell therapy is a remarkable achievement of modern science currently used to replace damaged tissues and/or organs, and appears promising for many diseases, including diabetes, retinitis pigmentosa, Parkinson's disease, hematological cancers including myocardial infarction, lymphoma and leukemia, bone marrow failure syndromes including anemia and cytopenia, hereditary immune disorders including Wiscott-Aldrich syndrome (WAS) and severe combined immunodeficiency (SCID), abnormal hemoglobin disorders including thalassemia, sickle cell anemia and congenital dysplasia, hereditary metabolic disorders including lysosomal storage disorders, galactosemia, phenylketonuria and glycogen storage disorders, neurological disorders including neuromyelitis optica, cartilage replacement including knee replacement, and Crohn's disease. Like organ transplantation, cell therapy also faces challenges of limited donor availability and immune rejection. This necessitates the development of mechanisms that make cells immunely privileged. Immune privileged cells not only enable the creation of "off-the-shelf" cell products, but can also lead to the creation of "off-the-shelf" organs. Universal cells are cells that can be administered to any patient without triggering an immune response. This has been the ultimate goal of organ transplantation and cell therapy since the development of these fields. The lack of universal cells generally limits off-the-shelf therapy and reduces many therapies to tight tissue matching between donor and recipient. In almost all cases, immunosuppressants are administered with significant side effects. An obvious side effect of immunosuppressant administration is increased general susceptibility to infections and cancer. Commonly used immunosuppressants include cyclosporine, azathioprine, anti-lymphoblast, anti-thymocyte globulin, muromonab-CD3, and porcine anti-lymphoblast globulin (P-ALG). Cyclosporine is known to cause nephrotoxicity, hepatotoxicity, hyperkalemia, hypertension, tremor, gingival hypergrowth, and hirsutism. Azathioprine suppresses bone marrow suppression, leading to leukopenia. Anti-lymphoblast and anti-thymocyte globulins are exogenous antibodies that can cause allergic reactions, such as fever, chills, and hypotension. The initial side effects of monoclonal antibodies (muromonab-CD3, OKT3) are similar to those of P-ALG. These include high fever, chills, headache, rigidity, and hypotension. Min, D.I. and Monaco, A. P. (1991), Complications Associated with Immunosuppressive Therapy and Their Management. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy, 11: 119S-125S. This technical field includes many examples of attempts to produce cells compatible with any recipient. The most common approach is beta-2 microglobulin (B2M) interference, which eliminates the surface expression of all class I molecules but leaves the cells vulnerable to lysis by natural killer (NK) cells. Insertion of the HLA-E gene at the B2M locus in human pluripotent stem cells (PSCs) confers inducible, regulated surface expression of HLA-E single-strand dimers (fused to B2M) or trimers (fused to B2M and peptide antigens) without the surface expression of any HLA-A, B, or C. These HLA-manipulated PSCs and their differentiated derivatives are not recognized as allogeneic by CD8 + T cells, do not bind to anti-HLA antibodies, and are resistant to NK-mediated lysis. Gornalusse, German G, Hirata, Roli K, Funk, Sarah E, Riolobos, Laura, Lopes, Vanda S, Manske, Gabriel, Prunkard, Donna, Colunga, Aric G., Hanafi, Laila-Aicha, Clegg, Dennis O. Turtle, Cameron, Russell, David W. ; HLA-E-expressing pluripotent stem cells escape allogenetic responses and lysis by NK cells, Nature Biotechnology (Vol 35 p 765) 2017/05/15/online; and Glas R, Franksson L, Ohlen C, Hoglund P, Koller B, Ljungren HG, et al. Major histocompatibility complex class I-specific and restricted killing of beta 2-microglobulin-deficient cells by CD8+ cytotoxic T lymphocytes. Proc Natl Acad Sci U S A. 1992;89(23):11381-5. Such approaches are genetic engineering approaches that prevent some cells from being recognized by the immune system but do not provide truly universal cells. Furthermore, potential cis-interactions between HLA-E and NKG2A and NKG2C may affect graft function and lead to suboptimal cell products. Furthermore, the cell-derived product is generated through multiple gene editing steps consisting of simultaneous knockout of all HLA class I molecules and knock-in of the HLA-E B2M fusion protein. Figures 1A to 1E are snapshots showing the stages of supramolecular activation cluster (SMAC) formation that lead to mature immune synapses.Figures 1A to 1E are snapshots showing the stages of supramolecular activation cluster (SMAC) formation that lead to mature immune synapses.Figures 1A to 1E are snapshots showing the stages of supramolecular activation cluster (SMAC) formation that lead to mature immune synapses.Figures 1A to 1E are s